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L Terenius

Publications and source records attributed to L Terenius.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice.

The kappa-opioid agonists U50488H, bremazocine, and BRL52537, and the mu-opioid agonist morphine were compared in their ability to modify spontaneous motor activity in male NMRI mice. Higher, analgesic doses of the kappa-agonists reduced rearing, motility, and locomotion in nonhabituated mice. These effects, as well as the analgesic action of U50488H, were blocked by the selective kappa-opioid antagonists nor-binaltorphimine and DIPPA. In contrast, lower, subanalgesic doses (1.25 and 2.5 mg/kg for U50488H; 0.15 and 0.075 mg/kg for bremazocine, and 0.1 mg/kg for BRL52537) time dependently increased motor activity. The stimulatory effects of U50488H and bremazocine were not observed in habituated animals and were reduced by dopamine depletion. Surprisingly, the stimulatory effects of U50488H and bremazocine were not blocked by nor-binaltorphimine and DIPPA but they were completely eliminated by naloxone (0.1 mg/kg). The effects of morphine were dose-dependent; an initial limited suppression was followed by increased motility and locomotion (but not rearing) with a peak effect at 20 mg/kg both in habituated and nonhabituated mice. The selective mu-opioid antagonist beta-funaltrexamine blocked morphine-induced motor stimulation and analgesia but failed to affect the analgesic and motor stimulatory effects of U50488H. The results indicate that kappa-opioid agonists interact with different functional subtypes of opioid receptors. A stimulatory, naloxone-sensitive but nor-binaltorphimine- and DIPPA-insensitive subtype of opioid receptor appears to operate only when the dopamine system is tonically active in nonhabituated animals. At higher doses, kappa-agonists produce analgesia and motor suppression, effects mediated by a "classic" (inhibitory) kappa-opioid receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Chronic ethanol enhances muscarinic receptor-mediated activator protein-1 (AP-1) DNA binding in cerebellar granule cells.

In this study we investigated effects of acute and chronic ethanol exposure on carbachol-induced activator protein-1 (AP-1) DNA binding in rat cerebellar granule cells. Acute ethanol application did not alter, whereas chronic ethanol exposure potentiated the carbachol-induced AP-1 DNA binding. The protein composition of the AP-1 transcription factor complex activated by carbachol stimulation of muscarinic receptors was analysed in control and chronic ethanol-exposed cells using a supershift assay with specific antibodies against c-Fos, Fos B, c-Jun, Jun B and Jun D proteins. Supershift analysis revealed that the carbachol-induced AP-1 complex was composed predominantly of Jun D and c-Fos. The composition of the AP-1 complex activated by carbachol in chronic ethanol-exposed cells did not differ from control. These findings indicate that chronic ethanol treatment can modulate carbachol-induced AP-1 DNA binding activity in cerebellar granule cells.

Animals↗
PubMed1999

Design, synthesis, and evaluation of Phe-Gly mimetics: heterocyclic building blocks for pseudopeptides.

Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics containing 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivatives (1-3) have the carboxylic acid function directly bound to the heterocyclic ring, and three derivatives (4-6) have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biologically active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH(2), SP). The pseudopeptide synthesis was performed using solid-phase methodology on a MBHA-resin using Boc-chemistry. The biological evaluation was performed by testing the micro- and delta-opioid receptor affinities of the dermorphin pseudopeptides and the NK(1) receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 3 were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the micro-receptor (IC(50) = 12-31 nM) in the same range as dermorphin itself (IC(50) = 6.2 nM). The agonist activity of three pseudopeptides at human micro-receptors was also evaluated. It was shown that the tested compounds retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC(50) > 1 microM) for the NK(1) receptor than SP itself (IC(50) = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.

Animals↗
PubMed1999

Binding of amyloid beta-peptide to mitochondrial hydroxyacyl-CoA dehydrogenase (ERAB): regulation of an SDR enzyme activity with implications for apoptosis in Alzheimer's disease.

The intracellular amyloid beta-peptide (A beta) binding protein, ERAB, a member of the short-chain dehydrogenase/reductase (SDR) family, is known to mediate apoptosis in different cell lines and to be a class II hydroxyacyl-CoA dehydrogenase. The A beta peptide inhibits the enzymatic reaction in a mixed type fashion with a Ki of 1.2 micromol/l and a KiES of 0.3 micromol/l, using 3-hydroxybutyryl-CoA. The peptide region necessary for inhibition comprises residues 12-24 of A beta1-40, covering the 16-20 fragment, which is the minimum sequence for the blockade of A beta polymerization, but that minimal fragment is not sufficient for more than marginal inhibition. The localization of ERAB to the endoplasmic reticulum and mitochondria suggests a complex interaction with components of the programmed cell death machinery. The interaction of A beta with ERAB further links oxidoreductase activity with both apoptosis and amyloid toxicity.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1999

A molecular model of Alzheimer amyloid beta-peptide fibril formation.

Polymerization of the amyloid beta (Abeta) peptide into protease-resistant fibrils is a significant step in the pathogenesis of Alzheimer's disease. It has not been possible to obtain detailed structural information about this process with conventional techniques because the peptide has limited solubility and does not form crystals. In this work, we present experimental results leading to a molecular level model for fibril formation. Systematically selected Abeta-fragments containing the Abeta16-20 sequence, previously shown essential for Abeta-Abeta binding, were incubated in a physiological buffer. Electron microscopy revealed that the shortest fibril-forming sequence was Abeta14-23. Substitutions in this decapeptide impaired fibril formation and deletion of the decapeptide from Abeta1-42 inhibited fibril formation completely. All studied peptides that formed fibrils also formed stable dimers and/or tetramers. Molecular modeling of Abeta14-23 oligomers in an antiparallel beta-sheet conformation displayed favorable hydrophobic interactions stabilized by salt bridges between all charged residues. We propose that this decapeptide sequence forms the core of Abeta-fibrils, with the hydrophobic C terminus folding over this core. The identification of this fundamental sequence and the implied molecular model could facilitate the design of potential inhibitors of amyloidogenesis.

Alzheimer Disease↗
PubMed1999

Biotransformation of nociceptin/orphanin FQ by enzyme activity from morphine-naive and morphine-treated cell cultures.

The biotransformation of nociceptin/orphanin FQ (NOFQ) by enzyme activity isolated from U1690 human lung carcinoma and SH-SY5Y human neuroblastoma cell lines, and from rat brain cortex cells in primary culture was investigated. The identification and quantification of the cleavage products were performed using electrospray ionization mass spectrometry linked to size-exclusion chromatography. The effect of chronic morphine treatment of the cells (5 days) on NOFQ biotransformation was also studied. It was found that major products generated from NOFQ were the amino-terminal peptides N1-9 and N1-13. The pattern of NOFQ biotransformation was quite similar for all three cell cultures. However, different proportions of the formed peptides were noted. The cleavage was inhibited by EDTA, PMSF, Hg2+, Cu2+ and Zn2+. Dynorphin A2-13 inhibited NOFQ cleavage in a manner suggesting competition of the two peptides for the same enzyme. Chronic morphine treatment of the cell cultures resulted in a substantial increase in the enzyme activity, leading to higher levels of the major fragments and accumulation of N1-12 and the shorter peptides N1-5, N1-6. Since the effect of morphine treatment of the cells was blocked by naloxone, it is likely that it was receptor specific. Taken together, the findings suggest that a metallosensitive endopeptidase, the activity of which is increased by chronic morphine treatment of the cells, is responsible for the biotransformation of NOFQ with fragments N1-9 and N1-13 being the major products.

Amino Acid Sequence↗
PubMed1999

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides.

The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.

Animals↗
PubMed1999

In vivo metabolism of nociceptin/orphanin FQ in rat hippocampus.

The in vivo metabolism of the newly identified endogenous ligand for the ORL1 receptor, the opioid-like peptide nociceptin (orphanin FQ) in rat hippocampus was studied using size-exclusion chromatography linked to electrospray ionization mass spectrometry. The results show that nociceptin is metabolized step-wise in vivo into fragments (1-13) and (14-17) as well as (1-9) and (10-13), respectively. Interestingly, the (1-13) and (1-9) fragments have the same C-terminus, Arg-Ala-Lys, suggesting that this is a motif recognized by an enzyme which fragments the peptide in two consecutive steps. Injection of the (1-13) fragment into rat hippocampus had no effect on spatial learning or motor function under conditions where nociceptin is active, showing that this metabolic conversion reduces affinity for the ORL-1-receptor.

Amino Acid Sequence↗
PubMed1999

A novel neuron-specific DNA end-binding factor in the murine brain.

To characterize the distribution of transcription factor AP-1 and YY1 DNA-binding activities in the rat brain, the labeled target oligonucleotides were loaded on brain sections and after incubation and washing, the residual signal was registered by autoradiography. The binding was predominantly associated with neurons and was regionally specific with highest levels in the cerebellum, hippocampus, and piriform cortex. The identified binding factor was not, however, sequence-specific, but apparently recognized DNA ends and was activated by long double-stranded DNA. UV cross-linking identified the molecular mass of the factor to be about 80 kDa. The factor was not found in soluble brain extracts, suggesting its association with membranes or the nuclear matrix. Despite apparent similarities with Ku protein, which targets DNA-ends, the DNA end-binding activity was present in brains of Ku86- and Ku70-deficient mice. Since DNA end-binding factors are generally involved in DNA repair, the same function may be suggested for the novel factor identified in the present study.

Animals↗
PubMed1999

Amyloid beta-peptide polymerization studied using fluorescence correlation spectroscopy.

BACKGROUND: The accumulation of fibrillar deposits of amyloid beta-peptide (Abeta) in brain parenchyma and cerebromeningeal blood vessels is a key step in the pathogenesis of Alzheimer's disease. In this report, polymerization of Abeta was studied using fluorescence correlation spectroscopy (FCS), a technique capable of detecting small molecules and large aggregates simultaneously in solution. RESULTS: The polymerization of Abeta dissolved in Tris-buffered saline, pH 7.4, occurred above a critical concentration of 50 microM and proceeded from monomers/dimers into two discrete populations of large aggregates, without any detectable amount of oligomers. The aggregation showed very high cooperativity and reached a maximum after 40 min, followed by an increase in the amount of monomers/dimers and a decrease in the size of the large aggregates. Electron micrographs of samples prepared at the time for maximum aggregation showed a mixture of an amorphous network and short diffuse fibrils, whereas only mature amyloid fibrils were detected after one day of incubation. The aggregation was reduced when Abeta was incubated in the presence of Abeta ligands, oligopeptides previously shown to inhibit fibril formation, and aggregates were partly dissociated after the addition of the ligands. CONCLUSIONS: The polymerization of Abeta is a highly cooperative process in which the formation of very large aggregates precedes the formation of fibrils. The entire process can be inhibited and, at least in early stages, partly reversed by Abeta ligands.

Alzheimer Disease↗
PubMed1999

Nociceptin (1 - 7) antagonizes nociceptin-induced hyperalgesia in mice.

Nociceptin and its N-terminal fragment, nociceptin (1 7), were administered intrathecally (i.t.) into conscious mice. Nociceptin (3.0 fmol) produced a significant reduction in the nociceptive thermal threshold (hyperalgesia) measured as the tail-flick and paw-withdrawal responses. Nociceptin (1-7), injected i.t., at 150-1200 fmol had no significant effect. However, when nociceptin (1-7) (150 1200 fmol) was injected simultaneously with nociceptin (3.0 fmol), nociceptin-induced hyperalgesia was significantly reduced. Analgesia induced by a high dose (1200 pmol) of nociceptin was not antagonized by co-administration of nociceptin (1-7) (1200 fmol). These results suggest that N-terminal fragments of nociceptin formed endogenously could modulate the hyperalgesic action of nociceptin in the spinal cord.

Amino Acid Sequence↗
PubMed1999

Modulation of neurotransmitter release in the basal ganglia of the rat brain by dynorphin peptides.

Microinjection studies have found that although dynorphin peptides decrease dopamine release in the rat basal ganglia, the nonselective opiate antagonist naloxone produces the opposite effect. To investigate the contribution of the dynorphin pathways to a tonic modulation of dopamine release, a microdialysis study was undertaken, with probes implanted in the substantia nigra and the ipsilateral neostriatum. Perfusion of the substantia nigra with the nonselective antagonist naltrexone (NTX; 1-10 microM), the selective kappa-opoid receptor antagonist, nor-binaltorphimine (nor-BNI; 1-10 microM), and the selective mu-opioid receptor antagonist, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP; 1-10 microM) produced an increase in dopamine release, both in substantia nigra and neostriatum. nor-BNI also produced an increase in dynorphin B release, and a similar effect was observed with the higher concentration of NTX (10 microM). At the higher concentration of NTX and CTOP, an increase in glutamate release was also observed. Perfusion of the neostriatum with NTX, nor-BNI, or CTOP increased striatal dopamine, and dynorphin B release and increased dynorphin B in the ipsilateral substantia nigra. NTX and CTOP, but not nor-BNI, increased striatal glutamate and aspartate release. The kappa-opioid agonist U-50,488H (10 microM) induced a decrease in dopamine levels, both in the substantia nigra and neostriatum, and a paradoxical increase in striatal aspartate levels. Finally, systemic administration of NTX (4 mg/kg s.c.) in awake animals significantly increased striatal dopamine levels. The results suggest that opioid peptides, either dynorphins acting on kappa-opioid receptors or enkephalins acting on mu-opioid receptors, exert tonic inhibition on dopamine and dynorphin B release in both substantia nigra and neostriatum.

Animals↗
PubMed1998

Human prodynorphin gene generates several tissue-specific transcripts.

The present study analyzes the transcription of the human prodynorphin gene. Transfection experiments indicate that promoter activity for the 2.8 kb 'brain-type' human prodynorphin mRNA resides in the DNA region located 140-180 b upstream of the exon 1/intron A boundary and not 1.2 kb further upstream, as proposed by others [S. Horikawa, T. Takai, M. Toyosato, H. Takahashi, M. Noda, H. Kakidani, T. Kubo, T. Hirose, S. Tanayama, H. Hayashida, T. Miyata, S. Numa, Isolation and structural organization of the human preproenkephalin B gene, Nature 306, 1983, pp. 611-614]. The new data locates the human prodynorphin gene promoter for the brain-type mRNA in a position corresponding to the position of the rat prodynorphin gene promoter [J. Douglass, C.T. McMurray, J.E. Garett, J.P. Adelman, L. Calavetta, Characterization of the rat prodynorphin gene, Mol. Endocrinol. 3, 1989, pp. 2070-2078]. Three previously not described types of human prodynorphin mRNA of the same size, 2.8 kb, one expressed in fetal brain and two others in testis, were characterized in this study. These mRNAs are generated by alternative splicing of novel 5'-uppermost exons and transcription is probably initiated from other promoters. Human neuroblastoma SH-SY5Y and SK-N-MC cell lines previously used in studies of gene transcription have the 2.8 kb prodynorphin mRNA of adult brain alongside a more abundant, shorter 2.3 kb transcript. The latter transcript was also found in testis and in fetal brain. It lacked the 5'-part of the 2.8 kb mRNA including the signal peptide encoding sequence. The complex pattern of prodynorphin gene expression and its functional consequences are issues for further studies.

Base Sequence↗
PubMed1998

Nociceptin fails to affect heroin self-administration in the rat.

The recently isolated peptide nociceptin has a primary structure similar to that of opioid peptides. Early functional studies suggested that it may act in opposition to opioid systems. To determine whether nociceptin influences the rewarding properties of heroin, nociceptin was given intracerebroventricularly (i.c.v.) to rats trained to self-administer heroin. Rats (n = 8) were given doses of 0.01 microg, 0.1 microg, 1.0 microg and 10.0 microg in a Latin square design. None of the doses significantly affected heroin self-administration rates compared to vehicle. The highest dose of nociceptin used inhibited spontaneous locomotor activity, evidence that the peptide retained its biological activity after i.c.v. infusion. These studies suggest that nociceptin does not affect the rewarding value of heroin.

Animals↗
PubMed1998

Autoantigen Ku in the brain. Developmentally regulated expression and subcellular localization.

A double-stranded DNA end-binding factor with high levels of expression in brain and testis of adult mice was identified as the Ku protein, earlier described as an autoantigen in connective tissue diseases and found to be essential for recombination of the immunoglobulin genes and DNA repair. High Ku levels were found in the cerebellum and pituitary gland, lower levels in the hippocampus, hypothalamus and white matter structures. Ku levels were much higher in embryonic rat brain than in the adult brain, suggesting a role of the Ku protein in brain development. In embryonic rat brain, Ku was associated with cell nuclei, but was predominantly located in the cytosol in the adult rat cerebellum and hippocampus. The abundant expression of Ku in the brain suggests the involvement of Ku autoantibodies in the pathogenesis of neuropsychiatric complications in connective tissue diseases.

Animals↗
PubMed1998

Release of endogenous excitatory amino acids in the neostriatum of the rat under physiological and pharmacologically-induced conditions.

There is immunohistochemical evidence suggesting that glutamate (Glu) is released from nerve terminals and acts, via several receptor subtypes, as a major excitatory neurotransmitter in the cortico-striatal pathway of the rat. Aspartate (Asp) is also present in cortico-striatal neurons, but its role as a neurotransmitter has been questioned, since, in contrast to Glu, it has not been demonstrated in presynaptic vesicles. Glu and Asp can be found at submicroM concentrations in the extracellular compartment of most areas of the basal ganglia. Their concentrations are largely regulated by transport mechanisms, but also by a synaptotagmin-dependent exocytotic release, and are sufficiently high to occupy junctional and extrajunctional receptors. We have investigated whether Glu and Asp release in the neostriatum can be selectively modulated by different neuronal systems. Dopamine (DA) and cholecystokinin (CCK) selectively stimulate Asp release, via D1 and CCKB receptor subtypes, respectively. Also opioid kappa-agonists increase Asp release. We propose that the selective modulation of Asp release by D1-, CCKB- and kappa-agonists involves striatal neurons containing Asp, but not Glu. In contrast, local perfusion with the mu-opioid antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) increases both Glu and Asp release. This effect is probably exerted on cortico-striatal terminals, via presynaptic inhibitory mu-receptors. Thus, these results demonstrate that extracellular levels of Glu and Asp are modulated differentially by different neuronal systems, and suggest that in the neostriatum of the rat there are neuronal populations using Glu and/or Asp as messenger(s).

Animals↗
PubMed1998

Failure to replicate an association between a rare allele of a tyrosine hydroxylase gene microsatellite and schizophrenia.

An association between schizophrenia and a rare perfect ten-repeat allele, K1p, of a tetranucleotide microsatellite polymorphism in the tyrosine hydroxylase gene has recently been reported. The rare allele was found only in schizophrenic patients. During treatment with antipsychotic drugs patients with the rare allele displayed lower plasma homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels than those without. We examined Swedish schizophrenic patients (n = 117) and healthy control subjects (n = 76) for the same polymorphism. In contrast to the previous studies, the K1p frequency in patients (4 of 117) tended to be lower than among controls (9 of 76). With all six alleles (K1p, K1i, K2-5) considered there was a significant difference between schizophrenic patients and control subjects. There was no significant difference in HVA and MHPG levels in cerebrospinal fluid from a subset (n = 64) of control subjects with and without the rare allele. The discrepant results warrant further investigation of the tyrosine hydroxylase gene.

Alleles↗